Flaviviruses are significant human pathogens for which no commercially approved vaccines exist. Flaviviruses exist as small (50 nm) icosahedral particles containing a single RNA molecule encoding 3 structural proteins (C, M and E) that make up the virion, and 7 nonstructural proteins required for genome replication. This virus family includes a number of mosquito-borne viruses that are pathogenic for humans, including West Nile virus (WNV), dengue virus (DENV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV). Each virus is endemic in regions with a large and highly susceptible population, causing significant medical and economic burden.
DENV has four known serotypes (1-4) that have defined global distribution. However, modern travel has altered the pattern and introduced DENV into naive populations. Over the past 50 years, dengue virus has become the most significant arbovirus human pathogen in the world because of its unusual transmission cycle involving a human host for amplification. There are currently 2.5 billion people living in dengue endemic regions with roughly 100 million annual cases of dengue fever and hundreds of thousands of cases of dengue hemorrhagic fever and dengue shock syndrome (Gubler, Clin. Microbiol. Rev. 11:480-496, 1998).
No vaccines are currently commercially available against any of the four DENV serotypes (DENV 1-4) largely because vaccine production is hampered by the fact that neutralizing antibodies to one serotype do not effectively neutralize the remaining DENV serotypes (Halstead and O'Rourke, J. Exp. Med. 146:201-217, 1977). In fact, low levels of these antibodies may actually increase the risk for more severe disease during secondary infection due to a phenomenon known as antibody dependent enhancement (ADE), which occurs when antibodies against one DENV serotype bind in a non-neutralizing manner to DENV particles of another serotype. This binding allows increased infection of Fc receptor-bearing cells, such as macrophages, which can change the infection profile of the virus or cause a release of chemokines leading to dengue hemorrhagic fever or dengue shock syndrome (Halstead and O'Rourke, J. Exp. Med. 146:201-217, 1977). Thus, a need exists for the development of a broadly protective dengue virus vaccine.